Abnormal Serum Free Light Chain Ratios Are Associated with Earlier Time to First Treatment and Poor Survival in Patients with Chronic Lymphocytic Leukaemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3141-3141
Author(s):  
Guy Pratt ◽  
Graham Mead ◽  
Supratik Basu ◽  
Abe Jacobs ◽  
Roger Holder ◽  
...  

Abstract Introduction: Serum free light chains (sFLC) have prognostic significance in plasma cell disorders. In B-cell chronic lymphocytic leukemia (CLL), a small study found 8/18 (44%) of patients to have abnormal FLC ratios but no assessment of prognostic value was published. The aim of the present study was to determine whether abnormal serum FLC concentrations are indicative of a poor prognosis in CLL patients. Methods: Sera were analysed from 381 previously diagnosed CLL patients (Stage A 307; B 30; C 26; 18 missing; male: Female Ratio 1.6:1, mean age 71 (29–98)) with samples taken before their first treatment (303) or after treatment (78). The study was approved by the Birmingham Heart of England NHS Trust Review Board. Patients were described using the Binet staging system and measured for prognostic markers including CD38, Zap70, mutational status, β2M and FLC. Kaplan Meier survival curves and Cox proportional hazards regression (age, sex, CD38, Zap 70, mutational status, β2M and sFLC) were calculated using SPSS v14. Results: 147/381 (39%) patient sera had abnormal sFLC ratios. Kaplan Meier analysis of all deaths showed abnormal ratios were significantly associated with worse survival (n=350, p<0.001). Analysis of deaths attributed to CLL (n=30) also indicated that an abnormal FLC ratio was predictive of shorter survival (p=0.001). However, for deaths not attributed to CLL (n=32), the FLC ratio was not significantly predictive of outcome (p=0.112). For Cox regression analysis (n=228) of deaths attributed to CLL only, three significant, independent, prognostic factors were identified: CD38 (p<0.001), abnormal ratio (p<0.001) and Stage (p=0.027). Analysis of the untreated patient population (n=303), using Kaplan Meier analysis of time to first treatment, found that an abnormal lambda ratio (p=0.04) but not an abnormal kappa ratio (p=0.443) predicted earlier treatment. For patients with an abnormal lambda ratio, the mean time to first treatment was 38 months earlier than those patients with a normal ratio. Cox regression analysis (n=171) of time to first treatment, found 4 significant, independent factors predicting earlier treatment: Zap70 (p<0.001), Age (p<0.001), abnormal sFLC ratio (p=0.001) and Stage (p=0.027). Conclusions: As shown in other monoclonal gammopathies, abnormal sFLC ratios were associated with poorer outcomes in patients with CLL. Furthermore, in an untreated population, patients with an abnormal lambda sFLC ratio required earlier treatment, indicating a pathological mechanism which is as yet unclear but which warrants further investigation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2631-2631
Author(s):  
Chaim Shustik ◽  
Stephen Harding ◽  
Keyue Ding ◽  
Liting Zhu ◽  
Laura Z. Rassenti ◽  
...  

Abstract Abstract 2631 Poster Board II-607 Introduction The measurement of immunoglobulin serum free light chains (sFLC) has prognostic value in the spectrum of plasma cell dyscrasias and has been evaluated in other B-cell malignancies. Its utility as a biomarker of potential prognostic value in B-CLL ( chronic lymphocytic leukemia ) was previously reported in a study of 259 patients in whom 39% had an abnormal sFLC ratio which was associated with a shorter time to first treatment and poor survival (Pratt et al. BJH. 2008). The objective of the present analysis was to identify if these findings are applicable to a previously untreated population of 125 patients accrued to NCIC CTG trial CL2 treated in a uniform manner and characterized for cytogenetic abnormalities, ZAP-70 expression and IgVH mutational staus. Patients & Methods Sera from 125 untreated patients, previously enrolled in a non-randomised, non-blinded, phase II study evaluating the efficacy of oral fludarabine (NCIC CTG CL2 trial), were analysed retrospectively. Median age was 61 yrs (range: 33–92) and 39% patients (49) were female. Rai staging system - Stage I: n=30, II: n=54, III: n=19, IV: n=22. Kaplan-Meier survival curves and log-rank test were used in summarizing and comparing survival distributions between sFLC ratio normal and abnormal groups, and COX regression analysis adjusting for prespecified baseline factors of ZAP-70, IGVH mutational status, sFLC and b2M were also performed to compare the two groups. Results 83/125 (66%) patients showed an abnormal sFLC ratio (<0.26 or >1.65). Table 1 summarises the results. b2M was the only baseline factor showing a statistically significant association with the sFLC ratio (p=0.01). A total of 33 patients died over the course of the study (21 had an abnormal sFLC ratio vs 12 with a normal sFLC ratio), including 20 deaths attributed to the disease and/or its treatment (13 with abnormal sFLC ratios vs 7 with normal sFLC ratios). No statistically significant difference was found, either for overall survival (OS) or for treatment free survival (TFS) between patients with normal and abnormal sFLC ratios. However, patients with abnormal sFLC ratios did show a borderline significantly worse progression free survival (PFS) (HR= 1.48, 95% C.I. 0.97 – 2.28, p = 0.07), even after adjustment for pre-specified baseline factors (HR = 1.48, 95% C.I. 0.94 -2.34, p = 0.09). Furthermore, in patients with mutated IGVH, those with with an abnormal sFLC ratio had a significantly shorter PFS (HR = 2.76, 95% V.I. 1.1 – 6.9, p=0.02). COX regression analysis for OS found that age (> 65yrs), gender (male), and stage (III or IV) were poor prognostic factors. sFLC ratios were not significantly associated with response rates (60% vs. 69%, p = 0.33) Conclusions 1) In this study of patients with untreated CLL with an indication for therapy, the frequency of an abnormal sFLC ratio is higher than previously reported i.e. 66% vs 44% (Martin et al. Trans Res. 2007) and 39% (Pratt et al. BJH. 2009). 2) The relation between IgVH mutational status and sFLC ratio needs further investigation. 3) The role of sFLC ratio as a prognostic biomarker in CLL should be evaluated in prospective trials of therapy in CLL. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4671-4675 ◽  
Author(s):  
Chung-Che Chang ◽  
Jennifer Lorek ◽  
Daniel E. Sabath ◽  
Ying Li ◽  
Christopher R. Chitambar ◽  
...  

In this study, we evaluated the prognostic significance of multiple myeloma-1/interferon regulatory factor-4 (MUM1/IRF4) expression in B-cell chronic lymphocytic leukemia (B-CLL). Our results demonstrated that the absence of MUM1/IRF4 expression showed the highest relative risk among the factors analyzed in determining the probability for death in patients with B-CLL using univariate and multivariate Cox regression analysis. Patients without MUM1/IRF4 expression had significantly worse overall survival than did those with MUM1/IRF4 expression (52% cumulative survival, 63 months vs not reached, Kaplan-Meier survival analysis; P < .03, log-rank test). Patients with MUM1/IRF4 expression were more likely to have disease at low Rai stage and interstitial/nodular marrow involvement. Furthermore, only 1 of 11 patients with MUM1/IRF4 expression and interstitial/nodular marrow involvement died during a 100-month follow-up. Our results suggest that B-CLL with expression of MUM1/IRF4, indicative of postgerminal center origin, has a more favorable clinical course and that MUM1/IRF4 is an important prognostic marker in B-CLL.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2355-2355 ◽  
Author(s):  
Guy Pratt ◽  
Stephen Harding ◽  
Chris Fegan ◽  
Chris J Pepper ◽  
David Oscier ◽  
...  

Abstract Abstract 2355 Poster Board II-332 An abnormal serum FLC ratio at presentation has been shown to be prognostic in chronic lymphocytic leukaemia (Pratt et al, 2009). Here we further analyse a retrospective cohort of 259 CLL patients (Stage: A, 209; B 23, C, 21; Male: Female ratio 1.6:1, mean age 75: Range 29-98). The levels of FLC and B2M were assessed using nephelometric immunoassays (The Binding Site, Birmingham UK) on the Siemens Dade Behring BN‘II analyser. Previously recorded measurements for biological and clinical markers (age, sex, CD38, Zap70, and VH mutational status) were used to produce Kaplan Meier Survival Curves and in Cox Regression analysis. We have identified that a cut-off above 50mg/L (in the context of an abnormal ratio to exclude renal effects) identifies a cohort of patients with progressive disease and a significantly poorer outcome. A total of 38 out of the 259 patients had serum FLC > 50mg/L. CLL patients with serum FLC >50mg/L had the following characteristics Stage A/B/C (26/5/5 + 2 unknown), Mutated vs Unmutated (19 vs 13, 6 unknown), Zap70 pos vs neg (19 vs 16, 3 unknown), CD38 pos vs neg (13 vs 23, 2 unknown) and 32 out of the 38 patients have progressed to treatment. Median time to first treatment for the CLL cohort with >50mg/L serum FLC was 83 months compared to 241 months for the CLL patients with normal FLC (p=9.8×10−6). Median overall survival was also significantly shorter for patients with an abnormal ratio and >50mg/L serum FLC (p=7.6 × 10−7). Cox regression analysis on the above population gave stage (Hazard ratio 3.9 p=<0.001), Zap 70 (Hazard ratio 1.9, p=0.001) and abnormal ratio with production above 50mg/L (Hazard ratio 1.9 p=0.009) as the only independent prognostic variables. Importantly >50mg/L FLC production is independent of both Zap70 and Vh mutational status as an indicator of time to first treatment. This study shows that in an unselected population of CLL patients serum FLC >50mg/L can independently identify a group of CLL patients with progressive disease and a poorer outlook. Disclosures: Harding: The Binding Site Group Ltd: Employment. Bradwell:The Binding Site Group Ltd:. Mead:Binding Site UK Ltd: Employment.


2020 ◽  
Author(s):  
Ren Wang ◽  
Meiqiu Wang ◽  
Zhengkun Xia ◽  
Chunlin Gao ◽  
Zhuo Shi ◽  
...  

Abstract Background Currently, studies to data in MN are consistent with complement activation has an essential role in mediating renal injury, and the LP is considered to be the principal pathway in PMN. CP activation initiated by C1q which deposits are suggestive of SMN. However, C1q deposition together with IgG and C3 granular deposit is found in many cases of PMN. Currently, the clinical and prognostic significance of C1q deposition in PMN is unclear. Therefore, we conduct this single-center research to explore the clinical and prognostic significance of C1q deposition in children with PMN. Method: 73 patients with C1q deposition were enrolled in this study. According to the “Case-control matching principle”, 73 patients without C1q deposition during the same period of the renal biopsy were selected as a control group. The clinical and pathological characteristics, treatment response, and long-term renal prognosis were compared between patients with and without C1q deposition. Result A total of 146 pediatric patients with PMN included with 86 men(58.9%) and 60 women (41.1%). The median age at onset was 15.0 (14.0—16.0) years. During an average follow-up of 52.4 ± 35.6 months, 8 patients (5.5%) progressed ESKD, 12 (8.2%) patients developed ESRD or renal dysfunction. The frequency of glomerular C4 deposits in the C1q deposits group was significantly higher than no C1q deposits group (34.2% vs 5.5%, p = 0.000). There were no other distinct differences in clinical and pathological characteristics between the two groups. Glomerular IgG subclasses were available in 79 patients, there was no difference in the glomerular IgG subclass distribution between the two groups (p IgG1=0.468,p IgG2=1.000༌p IgG3=0.988༌p IgG4=0.216). The Kaplan-Meier survival analysis found that there was no difference in the renal survival of ESRD (p = 0.415) and a combined event of ESRD and/or renal dysfunction (p = 0.214) between the two groups. The logistic regression analysis (p = 0.553) and Cox regression analysis (p = 0.618) revealed that C1q deposition failed to associate with renal dysfunction. Conclusion The CP does occur in some patients of PMN. However, it may be unrelated to the progression of the disease.


2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Xiaochun Xia ◽  
Chao He ◽  
Anqing Wu ◽  
Jundong Zhou ◽  
Jinchang Wu

Microtubule-associated protein 4 (MAP4) plays an important role in microtubule assembly and stabilization. The purpose of this study was to investigate the level of expression of MAP4 in lung adenocarcinoma (LADC) samples and to evaluate its prognostic value and the influence on cancer progression in LADC patients. The expression of MAP4 protein was analyzed using immunohistochemistry. The clinical significance and the prognostic significance of MAP4 expression were assessed by Kaplan-Meier analysis and Cox regression analysis. The roles of MAP4 in the migration and invasion of LADC cells were detected by wound-healing assays and transwell assays, respectively. We found the expression levels of MAP4 protein in LADC tissues to be significantly higher than those in noncancerous tissues. MAP4 expression was significantly correlated with differentiation, pathological T stage, and TNM stage. Kaplan-Meier survival analysis indicated that patients with high MAP4 expression had significantly poorer overall survival (OS). Cox regression analysis revealed that MAP4 expression level was an independent prognostic factor for OS. Functionally, in vitro studies showed that MAP4 knockdown efficiently suppressed the migration and invasion of LADC cells. Our data indicated that MAP4 protein may represent a novel prognostic biomarker and a potential therapeutic target for LADC.


2021 ◽  
Vol 7 (5) ◽  
pp. 3896-3904
Author(s):  
Daoting Deng ◽  
Hong Zhang ◽  
Junxi Liu ◽  
Lina Ma ◽  
Xinrui Lei ◽  
...  

To explore exosomal miR-375 expression in gastric cancer patients and its relationship with patient prognosis. A total of 53 patients diagnosed with gastric cancer in our hospital from May 2014 to May 2016 were included as the gastric cancer group, and 46 healthy women who came to our hospital for physical examination during the same period were enrolled as the healthy group. Exosomal miR-375 expression level was detected using qRT-PCR, and the diagnostic performance and prognostic significance of exosomal miR-375 in gastric cancer were explored. The gastric cancer group showed increased exosomal miR-375 expression than the healthy group (P< 0.05); Kaplan-Meier survival analysis exhibited that serum exosomal miR-375 has an AUC of 0.778, sensitivity of 69.57%, and specificity of 75.47%, whereas Cox regression analysis showed that the miR-375 expression in exosomes was an independent risk factor affecting the prognosis of gastric cancer patients (P< 0.05). Patient with gastric cancer showed upregulated miR-375 expression in serum exosomes. Serum exosomal miR-375 was found to has positive sensitivity and specificity in the diagnosis of gastric cancer, which may be associated with poor prognosis of gastric cancer patients.


Author(s):  
Nattinee Charoen ◽  
Kitti Jantharapattana ◽  
Paramee Thongsuksai

Objective: Programmed cell death ligand 1 (PD-L1) and mammalian target of rapamycin (mTOR) are key players in host immune evasion and oncogenic activation, respectively. Evidence of the prognostic role in oral squamous cell carcinoma (OSCC) is conflicting. This study examined the associations of PD-L1 and mTOR expression with 5-year overall survival in OSCC patients. Material and Methods: The expressions of PD-L1 and mTOR proteins were immunohistochemically evaluated on tissue microarrays of 191 patients with OSCC who were treated by surgery at Songklanagarind Hospital, Thailand from 2008 to 2011. Cox regression analysis was used to determine independent prognostic factors. Results: PD-L1 expression was observed in 14.1% of cases while mTOR expression was present in 74.3% of cases. Females were more likely to have tumors with PD-L1 (p-value=0.007) and mTOR expressions (p-value=0.003) than males. In addition, lower clinical stage and well differentiated tumor are more likely to have mTOR expression (p-value= 0.038 and p-value<0.001, respectively). Cox regression analysis showed that age, tumor stage, nodal stage, combined surgical treatment with radiation or chemoradiation therapy, surgical margin status, PD-L1 expression and mTOR expression are independent prognostic factors. High PD-L1 expression (hazard ratio (HR) 3.14, 95% confidence interval (CI), 1.26–7.79) and high mTOR expression (HR 1.69, 95% CI, 1.00–2.84) are strong predictors of poor outcome. Conclusion: A proportion of OSCC expressed PD-L1 and mTOR proteins. Expression of PD-L1 and mTOR proteins are strong prognostic factors of OSCC.


2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Jianye Tan ◽  
Haofeng Liang ◽  
Bingsheng Yang ◽  
Shuang Zhu ◽  
Guofeng Wu ◽  
...  

Osteosarcoma (OS) often occurs in children and often undergoes metastasis, resulting in lower survival rates. Information on the complexity and pathogenic mechanism of OS is limited, and thus, the development of treatments involving alternative molecular and genetic targets is hampered. We categorized transcriptome data into metastasis and nonmetastasis groups, and 400 differential RNAs (230 messenger RNAs (mRNAs) and 170 long noncoding RNAs (lncRNAs)) were obtained by the edgeR package. Prognostic genes were identified by performing univariate Cox regression analysis and the Kaplan–Meier (KM) survival analysis. We then examined the correlation between the expression level of prognostic lncRNAs and mRNAs. Furthermore, microRNAs (miRNAs) corresponding to the coexpression of lncRNA-mRNA was predicted, which was used to construct a competitive endogenous RNA (ceRNA) regulatory network. Finally, multivariate Cox proportional risk regression analysis was used to identify hub prognostic genes. Three hub prognostic genes (ABCG8, LOXL4, and PDE1B) were identified as potential prognostic biomarkers and therapeutic targets for OS. Furthermore, transcriptions factors (TFs) (DBP, ESX1, FOS, FOXI1, MEF2C, NFE2, and OTX2) and lncRNAs (RP11-357H14.16, RP11-284N8.3, and RP11-629G13.1) that were able to affect the expression levels of genes before and after transcription were found to regulate the prognostic hub genes. In addition, we identified drugs related to the prognostic hub genes, which may have potential clinical applications. Immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR) confirmed that the expression levels of ABCG8, LOXL4, and PDE1B coincided with the results of bioinformatics analysis. Moreover, the relationship between the hub prognostic gene expression and patient prognosis was also validated. Our study elucidated the roles of three novel prognostic biomarkers in the pathogenesis of OS as well as presenting a potential clinical treatment for OS.


2020 ◽  
Author(s):  
Xiaohong - Liu ◽  
Qian - Xu ◽  
Zi-Jing - Li ◽  
Bin - Xiong

Abstract BackgroundMetabolic reprogramming is an important hallmark in the development of malignancies. Numerous metabolic genes have been demonstrated to participate in the progression of hepatocellular carcinoma (HCC). However, the prognostic significance of the metabolic genes in HCC remains elusive. MethodsWe downloaded the gene expression profiles and clinical information from the GEO, TCGA and ICGC databases. The differently expressed metabolic genes were identified by using Limma R package. Univariate Cox regression analysis and LASSO (Least absolute shrinkage and selection operator) Cox regression analysis were utilized to uncover the prognostic significance of metabolic genes. A metabolism-related prognostic model was constructed in TCGA cohort and validated in ICGC cohort. Furthermore, we constructed a nomogram to improve the accuracy of the prognostic model by using the multivariate Cox regression analysis.ResultsThe high-risk score predicted poor prognosis for HCC patients in the TCGA cohort, as confirmed in the ICGC cohort (P < 0.001). And in the multivariate Cox regression analysis, we observed that risk score could act as an independent prognostic factor for the TCGA cohort (HR (hazard ratio) 3.635, 95% CI (confidence interval)2.382-5.549) and the ICGC cohort (HR1.905, 95%CI 1.328-2.731). In addition, we constructed a nomogram for clinical use, which suggested a better prognostic model than risk score.ConclusionsOur study identified several metabolic genes with important prognostic value for HCC. These metabolic genes can influence the progression of HCC by regulating tumor biology and can also provide metabolic targets for the precise treatment of HCC.


2015 ◽  
Vol 42 (3) ◽  
pp. 239-249 ◽  
Author(s):  
Kultigin Turkmen ◽  
Levent Demirtas ◽  
Ergun Topal ◽  
Abduzhappar Gaipov ◽  
Ismail Kocyigit ◽  
...  

Background: Atrial electromechanical delay (AEMD) times were considered independent predictors of cardiovascular morbidity among the general population. We aimed at evaluating AEMD times and other risk factors associated with 2-year combined cardiovascular (CV) events in HD patients. Material and Methods: Sixty hemodialysis (HD) and 44 healthy individuals were enrolled in this prospective study. Echocardiography was performed before the mid-week dialysis session for HD patients. Data were expressed as mean ± SD. Spearman test was used to assess linear associations. Survival was examined with the Kaplan-Meier method. Multivariate Cox regression analysis was used to determine the predictors of combined CV events in this cohort. Results: At the beginning of the study, left intra-atrial-AEMD times were significantly longer in HD patients compared to the left intra-atrial-AEMD times in healthy individuals. After 24 months, 41 patients were still on HD treatment and 19 (31.6%) had died. Serum triglyceride, total cholesterol and albumin were found to be higher and C-reactive protein (CRP) levels, left intra-atrial EMD time (LIAT) and interatrial EMD times were found to be lower in survived HD patients. With the cut-off median values of 3.5 g/dl for albumin, 0.87 mg/dl for CRP, 157 mg/dl for total cholesterol and 151 mg/dl for triglyceride, the Kaplan-Meier curves demonstrated significant differences in terms of all-cause mortality. We also demonstrated the Kaplan-Meier survival curves of HD patients according to tertile values of LIAT. Cox regression analysis revealed that increased CRP and higher LIAT were found to be independent predictors of combined CV events. Conclusions: Increased LIAT and inflammation were found to be closely associated with 2 years combined CV events and all-cause mortality in HD patients.


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